Design, synthesis, and cytotoxicity evaluation of novel thiophene, pyrimidine, pyridazine, and pyridine: Griseofulvin heterocyclic extension derivatives

Griseofulvin, an antifungal drug, has also shown good antiproliferative activity previously. This study was aimed to synthesize heterocyclic extension derivatives of griseofulvin and test them against cancer cell lines. Griseofulvin was hydrolyzed to afford griseofulvic acid (1) followed by hybridization with important heterocyclic moieties. Initially, the active methylene group of the 1,3-cyclohexanedione moiety in 1 was utilized to synthesize fused thiophene derivatives (4a and b) by reacting with malononitrile or ethyl cyanoacetate together with elemental sulfur. Compounds 4a and b were further converted to fused pyrimidine derivatives (5a-d) using ethyl isothiocyanate or phenyl isothiocyanate. Compound 1 was also reacted with aryldiazonium chlorides to synthesize compounds 6a and b, which were used to prepare fused thiophene derivatives (7a-d). The resulting thiophenes (7a-d) underwent cyclization to produce fused pyridazine derivatives (8a-d). In addition, fused pyridine derivatives (10a and b) were also prepared by the reaction of 4a and b with ethyl cyanoacetate using two different catalytic bases. The first was triethylamine to form 10a and b in two steps via 9a and b, and the second was sodium ethoxide to afford 10a and b in one step. Finally, 9a and b underwent cyclization in the presence of acetylacetone to yield compounds 11a and b. The structures of synthesized compounds were confirmed using IR, H-1 NMR, C-13 NMR, and mass spectrometry techniques. The synthesized compounds were subjected to cytotoxic screening against three tumor cell lines and presented good to excellent cytotoxic profiles. Compounds 4a and 11a showed significant inhibitory activity against the three cell lines compared to the standard drug doxorubicin.